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Updated: Jan 30, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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ONECUT2 is a driver of neuroendocrine prostate cancer

Haiyang Guo1, Xinpei Ci2,3, Musaddeque Ahmed4

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. allen100006@gmail.com.

Nature Communications
|January 19, 2019
PubMed

Insights

Neuroendocrine prostate cancer (NEPC) becomes aggressive due to ONECUT2 and hypoxia, driving resistance to therapy. Targeting hypoxia shows promise for treating this lethal disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Neuroendocrine prostate cancer (NEPC) is a lethal variant characterized by androgen receptor (AR) signaling loss and resistance to AR-targeted therapies.
  • NEPC shares clinical, genomic, and epigenetic similarities with other poorly differentiated neuroendocrine tumors (NETs).

Purpose of the Study:

  • To identify master transcriptional regulators of poorly differentiated NETs.
  • To investigate the role of ONECUT2 in NEPC pathogenesis and its interaction with hypoxia.
  • To evaluate the therapeutic potential of hypoxia-directed agents in NEPC.

Main Methods:

  • Pan-neuroendocrine tumor (NET) analyses to identify candidate regulators.
  • Ectopic expression of ONECUT2 in prostate adenocarcinoma models.
  • Assessment of androgen signaling, neuroendocrine plasticity, and hypoxia signaling pathways.
  • Evaluation of tumor growth inhibition using hypoxia-activated prodrug TH-302.

Main Results:

  • ONECUT2 was identified as a master transcriptional regulator of poorly differentiated NETs.
  • Ectopic ONECUT2 expression synergizes with hypoxia to suppress AR signaling and induce neuroendocrine plasticity in prostate cancer.
  • ONECUT2 activates SMAD3, which modulates HIF1α chromatin binding, increasing tumor hypoxia in NEPC.
  • Hypoxia-activated prodrug TH-302 demonstrated potent reduction of NEPC tumor growth.

Conclusions:

  • ONECUT2 and hypoxia act synergistically to drive NEPC aggressiveness and therapeutic resistance.
  • Targeting tumor hypoxia represents a promising therapeutic strategy for NEPC patients.

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